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Airway glucose homeostasis: a new target in the prevention and treatment of pulmonary infection

Emma H. Baker, PhD, FRCP; Deborah L. Baines, PhD
Author and Funding Information

Funding information

Professors Baker and Baines have received funding from the Medical Research Council (UK) MR/K012770/1; MR/J010235/1, British Lung Foundation COPD 10/7 and the Wellcome Trust (UK) WT075049AIA; 088304/Z/09/Z for some of the work described in this review

Conflicts of interest

The authors do not perceive any conflicts of interest relevant to the preparation of this manuscript

Institute of Infection and Immunity, St George’s, University of London, London, UK

Corresponding author Professor Emma H Baker, Institute of Infection and Immunity, St George’s, University of London, Cranmer Terrace, London, SW17 0RE, UK.


Copyright 2017, . All Rights Reserved.


Chest. 2017. doi:10.1016/j.chest.2017.05.031
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Abstract

In health, the glucose concentration of airway surface liquid (ASL) is 0.4mM, around 12 times lower than blood glucose concentration. Airway glucose homeostasis is a set of processes that actively maintain low ASL glucose concentration against the transepithelial gradient. Tight junctions between airway epithelial cells restrict paracellular glucose movement. Epithelial cellular glucose transport and metabolism removes glucose from ASL. Low ASL glucose concentrations make an important contribution to airways defence against infection, limiting bacterial growth by restricting nutrient availability.

Both airway inflammation, which increases glucose permeability of tight junctions, and hyperglycaemia, which increases the transepithelial glucose gradient, increase ASL glucose concentrations, with the greatest effect seen where they co-exist. Elevated ASL glucose drives proliferation of bacteria able to use glucose as a carbon source, including Staphylococcus aureus, Pseudomonas aeruginosa and gram-negative bacteria. Clinically this appears to be important in driving exacerbations of chronic lung disease, especially in patients with comorbid diabetes mellitus. Drugs can restore airway glucose homeostasis by reducing permeability of tight junctions (e.g. metformin), increasing epithelial cell glucose transport (e.g. beta agonists, insulin) and/or by lowering blood glucose (e.g. dapagliflozin). In cell culture and animal models these reduce ASL glucose concentrations and limit bacterial growth, preventing infection. Observational studies in humans indicate that airway glucose homeostasis modifying drugs could prevent chronic lung disease exacerbations if tested in randomised trials.


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